1. Field of the Invention
The present invention relates to a composition for preventing and treating cancer which comprises the extracts of Artocarpus altilis fruits, leaves, or stems, or the fractions thereof as active ingredients.
2. Description of the Related Art
In spite of the increase of incidence rate of cancer according to the development of human civilization, cancer treatment methods still depend on only surgical operation, radio-therapy and chemo-therapy using about 40 very strong cytotoxic anticancer agents. These treatment methods are only effective in early-stage cancer patients or are limited to specific cancers, so that they cannot hold back the increase of death rate of cancer.
Cancer is the most incurable disease, and the mechanism of cancer development and progress is closely related to other diseases such as vascular diseases, immune diseases, and rheumatism. Based on that conception, various anticancer agents and target mechanisms have been studied. A selective anticancer agent targeting a specific molecule is drawing our attention because it is not only safer and more effective in the treatment but also applicable to tailored medicine and combination therapy.
STAT3 is a transcriptional regulatory factor that regulates the expressions of genes involved in cell growth, differentiation, and apoptosis via intracellular signal transduction in relation to various cytokines and growth factors and also plays a certain role in transforming tumor cells into malignant cancer cells by over-expression and abnormal activation. The activation of STAT3 is triggered by the recognition of extracellular cytokines or growth factors (for example, EGF, PDGF, and IL-6, etc) by receptor proteins or by the phosphorylation by cancer inducing proteins such as Src or Ras, etc.
To activate STAT3, it is necessary the phosphorylation of tyrosine 705 by non-receptor proteins that usually phosphorylate the receptor proteins or tyrosine. The representative proteins that can phosphorylate tyrosine 705 of STAT3 are epidermal growth factor receptor (EGFR), Src, Janus activated kinase (JAK) activating enzyme, and extracellular signal-regulated kinase (ERK), etc.
As stated before, STAT is a signal transduction and transcriptional regulatory protein and is activated by the extracellular stimuli such as cytokines, hormones, and growth factors to lead the phosphorylation of tyrosine residue, during which it turns into dimer via the interaction with SH2 domain and then migrates into the nucleus to bind with a specific promoter. The STAT in the nucleus accelerates the expressions of cycline D and survivin, which play an important role in cancer cell growth, and also induces the expressions of Bcl-xL, Bcl-2, and Mcl-1, which suppress cancer cell apoptosis. STAT also accelerates the expression of VEGF playing an important role in cancer metastasis. The signal system of STAT can be stopped by dephosphorylation and protein degradation.
Active forms of three types of STAT proteins, STAT1, STAT3, and STAT5, are found in various cancers. In particular, STAT3 is activated not only in blood tumors including leukaemia but also in solid tumors such as breast cancer, head and neck cancer, melanoma, ovarian cancer, lung cancer, pancreatic cancer, and prostate cancer, suggesting that it can be an important target of cancer treatment (Hua Yu and Richard Jove, Nature Review Cancer (2004), 8, 945).
TABLE 1Tumor types(Activated STATBlood tumorsMultiple myelomaSTAT1, STAT3LeukaemiasHTLV-I-dependentSTAT3, STAT5ErythroleukaemiaSTAT1, STAT5Acute myelogenous leukaemia (AML)STAT1, STAT3, STAT5Chronic myelogenous leukaemia (CML)STAT5Large granular lymphocyte leukaemia (LGL)STAT3LymphomasSTAT3Non-Hodgkins lymphoma (NHL)STAT3Mycosis fungoidesSTAT3Cutaneous T-cell lymphomaSTAT3Anaplastic large-cell lymphoma (ALCL)STAT3Solid tumorsBreast cancerSTAT1, STAT3, STAT5Head and neck cancerSTAT1, STAT3, STAT5MelanomaSTAT3Ovarian cancerSTAT3Lung cancerSTAT3Pancreatic cancerSTAT3Prostate cancerSTAT3
Suppression of the activity of STAT3 thus is an important core technology in the development of effective and practical anticancer agents using the combination of anticancer mechanisms such as apoptosis induction (Catlett-Falcone R. et al., Immunity (1999), 10, 105), angiogenesis suppression (Niu, G. et al., Oncogene (2002), 21, 2000), and immune evasion blockage (Wang T. et al., Nature Medicine (2004), 10, 48). Therefore, greater therapeutic effect than what the conventional anticancer agent characterized by monologic action can be expected. STAT protein is not only involved in tumor related mechanisms but also involved in various other intracellular functions. So, the development of STAT inhibitor can be an important core technology for the development of immune inhibitors and even anti-diabetic agents. Major immune related functions of STAT have been disclosed by the experiment with a specific gene knock-out mouse. Related target genes have also been informed, which are as follows (Nature Review Cancer 9, 798, 2009).
TABLE 2KeyExampleSTATactivatorsMain target genesgenesSTAT1IFN, IFNa andTH1-typeTBX21, CD80,IFNβimmunostimulatoryCD40, IL-12,and pro-apoptosisCDKN1A andsome caspasesSTAT2IFNa andTH1-typeCD80 and CD40IFNβImmunostimulatoryand pro-apoptosisSTAT3IL-6, IL-10,TH17-type, anti-IL-17, IL-23,IL-23, IL-21,apoptosis,BCL-XL, BCL-2,IL-11, LIFpro-proliferation,MCL1, CCND1and OSMand metastasisand VEGFSTAT4IL-12TH1-type,IFNespecially IFNSTAT5IL-2, GM-CSF,Anti-apoptosis,BCL-XL, CCND2STAT5BIL-15, IL-7,pro-proliferationand FOXP3IL-3, IL-5,and differentiationgrowth hormonesand prolactinSTAT6IL-4 and IL-13TH2-type, and anti-GATA3 and BCL-2apoptosis
Researchers at Columbia University reported their study as “STAT3 reprograms neural stem cells along the aberrant mesenchymal lineage” (Nature 463, 318, 2010). STAT3 is one of the small genes involved in the proliferation of cancer stem cells, which means the gene regulates 6 typical functions of cancer, that are growth, metastasis, angiogenesis, apoptosis evasion, tissue penetration, and cell immortalization. It has been known that cancer stem cells are involved in cancer metastasis, treatment resistance, and recurrence. Therefore, recent study for the development of an anticancer agent is mainly targeting cancer stem cells.
The scientific name of breadfruit tree is Artocarpus altilis (Parkinson) Fosberg, and this tree has been used as a traditional folk medicine in Southeast Asia and Africa to treat sore eyes and sciatica. This natural medicine is recently tried to treat malaria or dengue fever as well. So, it can be said that breadfruit tree is being used to treat sore eyes and sciatica and is confirmed to be effective in treating malaria, yellow fever, and dengue fever, and is even used to treat liver cirrhosis, hypertension, and diabetes particularly in Indonesia (J. Agric. Food Chem. 60, 3867, 2012; Phytotherapy Res. 20, 1052, 2006).
The present inventors screened resources that could regulate the activity of STAT3 from various traditional natural medicines and afterward reported the result saying that cryptotanshinone of Salvia miltiorrhiza could regulate the phosphorylation of STAT to bring anticancer effect (Cryptotanshinone Inhibits Constitutive Signal Transducer and Activator of Transcription 3 Function through Blocking the Dimerization in DU145 Prostate Cancer Cells, Cancer Research 69, 193, 2009).
The present inventors have screened resources that could regulate the activity of STAT3 from natural materials. As a result, the inventors completed this invention by confirming that the extract of Artocarpus altilis or the fractions thereof could efficiently suppress the activity of STAT3 involved in the abnormal activity or over-expression in cancer cell lines of rectal cancer, prostate cancer, breast cancer, and colorectal cancer, with exhibiting the cancer cell growth inhibition effect, so that it could be effectively used in the treatment of diseases attributed to STAT3 activity and cancer.